Journal
CARDIOVASCULAR TOXICOLOGY
Volume 21, Issue 9, Pages 759-771Publisher
HUMANA PRESS INC
DOI: 10.1007/s12012-021-09667-w
Keywords
MicroRNA-17-5p; Cardiac hypertrophy; Mfn2; PI3K; AKT; mTOR pathway; Autophagy
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Funding
- Six Talent Peaks Project in Jiangsu Province, China [2016-WSN-103]
- Nantong Science and Technology Bureau, China [JC2018082, MS22018005]
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This study demonstrated that miR-17-5p inhibits Mfn2 expression, activates the PI3K/AKT/mTOR pathway, and suppresses autophagy to promote pathological cardiac hypertrophy.
Pathological cardiac hypertrophy is the leading cause of heart failure, and miRNAs have been recognized as key factors in cardiac hypertrophy. This study aimed to elucidate whether miR-17-5p affects cardiac hypertrophy by targeting the mitochondrial fusion protein mitofusin 2 (Mfn2)-mediated phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway and regulating autophagy. miR-17-5p expression was shown to be upregulated both in vivo and in vitro. In addition, a miR-17-5p inhibitor significantly reversed AngII-induced cell hypertrophy in neonatal rat left ventricle myocytes (NRVMs). In contrast to miR-17-5p expression, Mfn2 expression was inhibited in rat hearts at 4 weeks after transverse aortic constriction (TAC) and in an Ang II-induced cell hypertrophy model. We examined miR-17-5p targeting of Mfn2 by dual luciferase reporter and Western blot assays. In addition, we also verified the relationship between Mfn2 and the PI3K/AKT/mTOR pathway. Mfn2 overexpression attenuated miR-17-5p-induced cell hypertrophy, and in rat myocardial tissue, miR-17-5p induced autophagy inhibition. In summary, the results of the present study demonstrated that miR-17-5p inhibits Mfn2 expression, activates the PI3K/AKT/mTOR pathway and suppresses autophagy to promote cardiac hypertrophy.
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